DESCRIPTION: Multifunctional CaM kinase is activated by many neurotransmitters, hormones and growth factors that elevate intracellular free Ca2+. The kinase responds to these Ca2+-linked signal transaction systems by phosphorylating diverse substrates located in cytosolic, nuclear, cytoskeletal and membrane compartments. Its high concentration in brain, its implicated role in long-term potentiation and its regulation by autophosphorylation suggests that it may participate in neuronal plasticity and that it may function as a molecular memory device. Despite rapid advances in the field, however, many important biochemical and neuropharmacological issues remain unresolved, including: i) What is the mechanism of its biochemical memory -- how is the Ca2+- independent state of the kinase maintained in neurons? We will examine autophosphorylation that maintains its autonomous activity at basal Ca2+ and the autophosphorylation that desensitizes it to further stimulation. ii) Is the activity of CaM kinase and other calmodulin-dependent enzymes regulated by the availability of free calmodulin. We will test whether the limiting availability of calmodulin enables preferential activation of calcineurin over CaM kinase at low Ca2+. iii) What is the molecular basis for substrate specificity of CaM kinase isoforms and how do they differ from each other? We will determine the structural basis and functional consequence for the differential Ca2+/calmodulin sensitivity of a- and b-CaM kinase. iv) What are the functions of CaM kinase in brain? We will explore new strategies for inhibiting the kinase and examine its role in neurotransmitter release using mouse knockouts of CaM kinase and synapsin I.